Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1997-01-10
2001-02-06
Eisenschenk, Frank C. (Department: 1643)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C564S123000, C564S125000, C564S129000, C514S557000
Reexamination Certificate
active
06184414
ABSTRACT:
This application is based on DE Patent application 4424043.0 filed Jul. 11, 1994 and PCT/EP95/02600 filed Jul. 5, 1995 the contents of which are incorporated hereinto by reference.
The present invention is relative to a novel active substance valuable in animal nutrition and to mixtures containing the same in liquid form as well as to a process of their production. The invention concerns in particular a process of producing ammonium-2-hydroxy-4-methylthio-butyrate (MHAAS) by treating 2-hydroxy-4-methylthio-butyric acid (MHA) with ammonia, which MHA contains both monomers and dimers and higher oligomers and is isolated from a reaction mixture obtained by the attachment of hydrogen cyanide (HCN) to methylmercaptopropionaldehyde (MMP) and by mineral-acidic hydrolysis of the methylmercaptopropionaldehyde cyanohydrin (MMP-CH) obtained thereby.
BACKGROUND OF THE INVENTION
Nourishment-improving feedstuff additives are an indispensable component of animal nutrition today. They serve for a better utilization of the food offered, stimulate growth and promote protein formation. One of the most important of these additives is the essential amino acid methionine, which is quite important as adjuvant especially in the raising of poultry. However, so-called methionine substitutes are becoming increasingly significant in this area since they have growth-stimulating properties similar to those of amino acids known for such properties.
Among these substitutes 2-hydroxy-4-(methylthio)-butyric acid is known as
m
ethionine-
h
ydroxy
a
nalogue, abbreviated MHA, in racemic form as additive and has become economically significant.
MHA is obtained and used in the form of aqueous solutions with active-substance contents between approximately 88-90%. However, these concentrates contain not only the monomeric acid but also, as a consequence of inner-molecular esterification, oligomers, primarily linear and cyclic dimers as well as, to a lesser extent, tri- and tetramers. It is desirable on account of the known, lower nutritive efficiency of action and the poorer rheological behavior to keep the oligomer content as low as possible. On the other hand, the formation of oligomers is subject, as are all &agr;-hydroxy acids, to the laws of chemical equilibrium and their amount can therefore not be freely selected. Rather, it is a function of the parameters such as concentration, temperature, pH and water content which determine the adjustment of the equilibrium. It is possible to obtain products with a distinctly lower oligomer portion than corresponds to the equilibrium due to the inertia of the equilibration reaction under suitable conditions; the ratio of monomers to the sum of the oligomers is then usually above 4:1 and can even reach values above 5:1. However, the ratio constantly shifts after a fairly long storage in favor of the oligomers until finally, after the adjustment of equilibrium has been completed, the monomer portion has dropped to approximately 2.5 to approximately 3:1 as a function of the water content, temperature and pH. The product “ages”.
This ageing process also constitutes an application-specific disadvantage of commercial MHA.
Another production-specific disadvantage is the compulsory accumulation of inorganic ammonium salts associated with the obtention of MHA. Thus, in the production process customary today in the art approximately the same amount of ammonium sulfates are produced per kg MHA as waste-water ballast (see below). However, their removal or workup for being utilized elsewhere is associated with additional expense which makes the process and therewith the target product considerably more expensive.
The methionine substitutes also include certain salt-like compounds of MHA such as, in particular, its calcium salt and mixed calcium ammonium salt. However, they have not achieved the same commercial significance as the free acid, since their production is associated with higher production costs. In addition, they can not be added as simply and homogeneously as powdery, slightly hygroscopic solids into the feedstuff mixtures as the readily sprayable, aqueous concentrates of the free acid.
A further additive of this substance class is ammonium-2-hydroxy-4-(methylthio)-n-butyrate, abbreviated MHAAS. Although it has been known for a rather long time, MHAAS has not been accepted as yet in animal nutrition. This is probably connected in particular with the fact that the salt in its pure form can be isolated only with difficulty and with considerable expense and is obtained either as a viscous oil or as a deliquescent and hygroscopic mass. Also, the handling of such a substance which tends toward inhomogeneity poses problems in the area of application technology, for which reason it is difficult to exactly determine its biological merit. In any case, there has as yet been no secure knowledge about its nutritive equivalence in relation to current market products.
2-hydroxy-4-(methylthio)-n-butyramide, abbreviated MHA amide, is also known as a methionine substitute. However, the purposeful production of the compound, which occurs as intermediate stage in the MHA process, and the separation from the hydrolysis mixtures turn out to be very difficult. Low yields of crystalline MHA amide as well as its nutritive efficiency, which is less compared to that of MHA itself, are also reasons why this substance has remained insignificant commercially.
The general process for producing MHA and its alkaline/alkaline-earth salts starts with 3-methylmercaptoproprionaldehyde, also designated as MMP, which is nitrilized with hydrogen cyanide to 2-hydroxy-4-methylthio-butyronitrile, also designated as MMP-cyanohydrin or MMP-CH (equation I).
The MMP-cyanohydrin produced is then hydrolyzed customarily with strong mineral acids such as H
2
SO
4
or HCl via the intermediate stage of 2-hydroxy-4-methylthiobutyramide, also designated as MHA, (equation II),
to the methionine hydroxy analogue (MHA) (equation III).
This hydrolysis can be carried out in one stage or in two. In order to arrive at the MHA salt the MHA present in the product mixture is treated in a suitable manner either directly or after previous isolation.
Such different separating techniques as solvent extraction, salting out, precipitation, filtration and concentration can be used for the isolation either individually or in combination.
The MHA acid present can be further processed to the desired MHA salt e.g. by being treated with metal oxides, -hydroxides, -carbonates. In order to arrive at the ammonium salt (MHAAS) MHA can be treated e.g. with ammonia (equation IV):
In any case, an important problem is to separate the particular target product from the inorganic accompanying substances and ballast substances, whose workup along with their utilization and removal presents a significant problem according to today's standards and can decisively influence the economy of the basic production process.
A great number of processes are described in the patent literature which have as their subject matter the obtention of MHA as such and also that of the alkaline/alkaline-earth salts, preferably of calcium- and mixed calcium ammonium salts.
The processes of European patents EP 142,488; 143,100; 330,521 and those of American publications U.S. Pat. Nos. 3,773,927 and 4,353,924 concern the production of MHA in the form of aqueous concentrates.
A two-stage hydrolysis starting from MMP-CH forms the basis of the processes of EP patent 142,488 (with sulfuric acid) and of EP patent 143,100 (with mineral acid). Cyanohydrine is hydrated therein at first at relatively low tepperatures with e.g. 50-70% sulfuric acid to MHA amide, whereafter the hydrolysis is completed at higher temperatures after dilution with water. Then the reaction mixture is decomposed by extraction, making use of certain solvents partially mixcible with water. MHA is then obtained from the organic extract in cncentrated, aqueous solution by evaporating the solvent under determined conditions in the presence of water. In this manner a high-quality end product is obtained at first
Kohl Heinz
Suchsland Helmut
Degussa - Aktiengesellschaft
Eisenschenk Frank C.
Pillsbury Madison & Sutro LLP
Zeman Mary K
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